Aralkyl-alcohol peiperazine derivatives and their uses as antidepressant

ABSTRACT

Aryl alkanol piperazine derivatives of the formula 
                         
and pharmaceutical compositions comprising the same. Also disclosed are methods for treating depression using the pharmaceutical composition. Compounds of the invention have excellent dual inhibitory actions to the uptake of the mono-amines neurotransmitter, good antidepressant activities and minor side effects.

FIELD OF INVENTION

The present invention relates to aryl alkanol piperazine derivatives andtheir applications as antidepressants.

TECHNICAL BACKGROUND

Depression is one of the most common mental diseases. The incidence ofthis disease is about 5% of the world's population and it seriouslyaffects our health and daily life. It is predicted that by 2020,depression will become the second most deadly illness that bothers ourwell-being and shortens our life span (second only to ischemic heartdiseases.)

Although many antidepressants have been used clinically, many patientsstill suffer from depression after treatment because of the poorefficacy and latent side effects of some drugs. For many patients,electricity convulsion treatment remains necessary. Therefore, thedevelopment of antidepressants is definitely among the top populartopics in new medicine research. Many pharmaceutical companies investmassive funds into developing better antidepressants. The pathogenesisof depression is unknown, but is thought to be related to transmissionimpediment of 5-Hydroxytrypta mine (5-HT) and noradrenalin (NA) atsynapses in the brain. Taking this point into consideration, theresearch of antidepressants usually focuses on enhancing thetransmission function of NA and 5-HT at synapses in the brain. Due tomany side effects of traditional TCA antidepressants, it will eventuallybe replaced by selective serotonin-reuptake inhibitors (SSRI) and othernew generations of antidepressants. In the past 20 years, the appearanceof SSRI, represented by fluoxetine, made a big progress in the treatmentof depression. The main advantages of this kind of antidepressants arefewer side effects, convenient administration, -- and better tolerance;therefore, it is usually chosen as the first-line treatment to mostpatients suffering from depression. Reboxetine, which was marketed forthe first time in 1997 in the United Kingdom, is the first drug ofselective Norepinephrine-reuptake Inhibitors (NARI). This drug hasbetter tolerance and better effects than SSRI in the treatment ofdepression. Another kind of new medicine is NA and specific 5-HTantidepressants such as Mirtazapine and Mianserine. These medicinesinvolve both serotonergic and noradrenergic enhancement through blockadeof the α2-autoreceptor and α2-heteroreceptor, increasing the release ofNA and 5-HT in the synapses. American Home Products, Inc. (AHP) releaseda new antidepressant drug under the tradename Venlafaxine in 1997, whichis the first one that is capable of inhibiting both NA and 5-HT reuptake(SNRI). Its characteristic is its rapid pharmacodynamic response. Thisis significant because slow response is seen as concern in other modernantidepressants. Venlafaxine has shown to be effective at treatingsevere and chronical depression. Compared with SSRI, the understandingof the SNRI compounds is limited.

Although different types of antidepressants have their own merits, itseems that there is no such drug that is particularly effective.Improvement is only made on their tolerance; and most of them havestrong inhibitory actions to the cytochrome P450 system. Therefore, theantidepressants on the market today still cannot satisfy the need oftreating depression. Many companies are studying different 5-HT subtypeacceptor inhibitors. In addition, the launch of dual-actingantidepressants have prompted efforts to develop new antidepressantshaving triple actions on 5-HT, NA and DA systems.

DESCRIPTION OF THE INVENTION

The first aspect of the present invention provides aryl alkanolpiperazine derivatives that overcome the defects of the existingantidepressants, such as insufficient antidepressant activity and strongantagonism to the cytochrome P450 system, to satisfy the needs ofdepression treatment.

The second aspect of the present invention provides methods of using theabove compounds as antidepressants.

The aryl alkanol piperazine derivatives described in the presentinvention are free base or salts of the compounds represented by thefollowing general formula:

in which the salts are one of hydrochloride, hydrobromide, sulfate,trifluoroacetate or methanesulfonate etc. Preferably the salt ishydrochloride or hydrobromide, and can contain about 0.5-3 molecules ofhydrate water.

Wherein

Ar₁ and Ar₂ independently represent:

each of R₁, R₂ and R₃ can represent any one of hydrogen, a C₁-C₃ alkylgroup, a C₅ or C₆ cycloalkyl group, a phenyl, substituted phenyl,hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen,carboxylic, carboxylic ester, nitryl or acetonitrile group.

R₁, R₂ and R₃ preferably represent one of hydrogen, a C₁-C₃ alkyl group,a hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen or nitrylgroup.

Y represents one of C, N, or O.

Z represents a five or six-member ring containing at least one of C, S,N or O; and

n=0, 1, 2, 3; m=1, 2, 3.

The unsymmetrical carbons of the structure may be achiral carbon atomsor chiral ones.

The preferable compounds are as follows:

IV-1 N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-2N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-3N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-4N¹-benzyl-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-5N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-6N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-7N¹-benzyl-N⁴-[2-(4-nitrophenyl)ethyl-2-ol]piperazine, IV-8N¹-benzyl-N⁴-[(1,2-diphenyl)ethyl-2-ol]piperazine, IV-9N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine,IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl)ethyl-2-ol]piperazine, IV-11N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-12N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2-ol)piperazine, IV-13N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-14N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-15N¹-[1-(4-nitrophenyl)ethyl]-N⁴-[2-(4-methylphenyl)ethyl-2-ol]piperazine, IV-16N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl-2- ol]piperazine,IV-17 N1-(3-chlorophenyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-18N1-(2-phenylethyl-2-ol)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-19N1-benzyl-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-20N1-(4-nitrobenzyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-21N1-(4-aminobenzyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-22N1-(3,4,5-trimethoxybenzyl)-N4-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-23N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-24N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-25N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-26N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-27N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-28N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-29N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-30N¹-(R-1-phenylethyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-31N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-32N¹-(S-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-33N¹-(S-1-phenylethyl)-N⁴-R-2-phenylethyl-2-ol)piperazine, IV-34N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-35N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-36N¹-benzyl-N⁴-(2-phenylethyl-2-ol)piperazine, IV-37N¹-(4-chlorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-38N¹-(4-chlorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-39N¹-benzyl-N⁴-[2-(4-methoxyphenyl)ethyl-2-ol]piperazine, IV-40N¹,N⁴-di(2-phenylethyl-2-ol)-piperazine, IV-41 N¹-(4-aminobenzyl)-N4-(2-phenylethyl-2-ol)piperazine, IV-42N¹-benzyl-N⁴-[(2-naphthyl) ethyl-2-ol]piperazine, IV-43N¹-benzyl-N⁴-[(3-phenyl)propyl-3-ol]piperazine, IV-44N¹-(2,4-dimethoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-45N¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-46N¹-benzyl-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-47N¹-(1-phenylpropyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-48N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-49N¹-(3,4-methylenedioxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-50N¹-(1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-51N¹-(S-1-phenylethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-52N¹-(R-1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine.

A preferable compound is IV-19N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine.

Their structures are shown in Table 1

TABLE 1 Code Ar₁ Ar₂ R₁ R₂ n m IV-1 Ph Ph H CH₃ 1 1 IV-2

Ph H CH₃ 1 1 IV-3 Ph Ph CH₃ CH₃ 1 1 IV-4 Ph

H H 1 1 IV-5

Ph H H 1 1 IV-6

Ph H H 1 1 IV-7 Ph

H H 1 1 IV-8 Ph Ph H Ph 1 1 IV-9

H H 1 1 IV-10 Ph

H H 1 1 IV-11

H H 1 1 IV-12

Ph CH₃ H 1 1 IV-13

Ph H H 1 1 IV-14

Ph H H 1 1 IV-15

CH₃ H 1 1 IV-16 Ph

H H 1 1 IV-17

0 CH₃ 0 1 IV-18

H CH₃ 1 1 IV-19 Ph

H CH₃ 1 1 IV-20

H CH₃ 1 1 IV-21

H CH₃ 1 1 IV-22

H CH₃ 1 1 IV-23*

Ph H H 1 1 IV-26*

Ph H H 1 1 IV-29* Ph Ph CH₃ H 1 1 IV-34 Ph

(S)CH₃ CH₃ 1 1 IV-35 Ph

(R)CH₃ CH₃ 1 1 IV-36 Ph Ph H H 1 1 IV-37

Ph H H 1 1 IV-38

H H 1 1 IV-39 Ph

H H 1 1 IV-40

Ph H H 1 1 IV-41

Ph H H 1 1 IV-42 Ph

H H 1 1 IV-43 Ph Ph H H 1 2 IV-44

Ph H H 1 1 IV-45* Ph Ph H H 1 1 IV-47 Ph Ph CH₂CH₃ H 1 1 IV-48

Ph H H 1 1 IV-49

Ph H H 1 1 IV-50* Ph

CH₃ H 1 1 *a racemic compound and its corresponding optical isomers

The compounds in this invention can be prepared as follows:

Piperazine is used as a starting material to prepare the above-mentionedcompounds. First, piperazine is reacted with the correspondinghalogenated arylalkane through the nucleophilic substitution reactionusing phase transfer catalysis to produce the N-monoalkylated compound(II). The reaction is carried out using hexadecyl trimethyl bromoa mine(CTAB) as a phase transfer catalyst, benzene/water is the solventsystem, and KOH for alkylation on one N atom of the piperazine ring,with a yield of 86%.

Compound (II) is alkylated at N⁴ with the corresponding halogenatedaralkylketone through the hydrocarbylation reaction to obtain thearalkylketone piperazine (III). When using K₂CO₃/DMF, the reaction cantake place at room temperature, and the yield is about 80%. If usingK₂CO₃/CH₃COCH₃, NaHCO₃/C₂H₅OH or Et₃ N/CHCl₃ as reaction systems, itneeds reflux for 8-24 h, the color of reaction will darken as timepasses, and prolonged reaction will reduce the quality and yield of theproducts. The main intermediate (III) can be obtained by the abovementioned processes.

Finally, the compound (III) is reduced with KBH₄ in CH₃OH under refluxfor 3-5 hours to give the corresponding aryl alkanol piperazine compound(IV), which also can be prepared directly from compound (II) by step c.The goal compounds IV-1 to IV-52 are obtained by the above mentionedprocedures.

The halogenated arylalkane and the halogenated arylformoxylalkylcompounds in steps a, b and c can be obtained commercially, and also beprepared by using bro mine or copper bromide with corresponding aralkylketones according to published conventional methods.

The aryl alkanol piperazine derivatives described in this invention havedual inhibitory actions on 5-HT and NA reuptake, and they can be used asantidepressant.

Pharmaceutical compositions comprising the derivatives described in thisinvention can be ad ministered to depression patients orally or viainjection and so on.

The pharmaceutical composition may comprise an effective amount of acompound of the invention with one or more pharmaceutically acceptablecarriers.

The carriers mentioned above include dilutents, excipents (water, etc),adhesives (fibrin derivatives, gelation, polyvinyl, pyrrolidone, etc),filling materials (starch, etc), disitegrants (calcium carbonate, sodiumbicarbonate, etc) and other auxiliary materials like flavor andedulcorant.

For oral administration, the compounds can be prepared as solidformulations, such as tablets, powders or capsules. For injection, theycan be prepared as a liquid form.

Each formulation of the compositions in this invention may be preparedby pharmaceutically conventional methods, and the content of the activecompound may be 0.1-99.5%.

The dosage of the compounds could be regulated according to varioustaking methods, the age and the weight of patients, and specific casesof diseases. Daily whole dosage can be 5-30 mg/kg (po) or 1-10 mg/kg(iv).

The derivatives in this invention demonstrated the antagonism todepression in the animal trials.

The inventors discover that derivatives of the present invention have abroader indication, a smaller side effect, a lower toxicity, and aslighter nerve side effect than the single action mechanismantidepressants used clinically at present like Desipra mine andFluoxetine.

EXAMPLES

General Preparation 1: N-aralkyl piperazine dihydrochloride (II)

A mixture of piperazine hexahydrate (350 mmol), solid KOH (100 mmol) andCTAB (Hexadecyl Trimethylammonium Bromide, 1 mmon) in water (18 ml) washeated to get a solution. Thereafter, aralkyl chlorine (100 mmol) in 140ml of benzene was added to the solution dropwise at 70° C., and refluxedfor 1-3 h. The organic layer was washed with water and saline, dried(mgSO₄), filtered and evaporated, the residue was dissolved by 50 ml ofethanol and adjusted to PH=3 with HCl/C₂H₅OH, and the resultingprecipitate was recrystallized from ethanol to obtain N-aralkylpiperazine dihydrochloride (55-86%).

General Preparation 2: N¹-aralkyl-N⁴-arylformoxylalkyl piperazinedihydrochloride (III)

A mixture of N-aralkyl piperazine dihydrochloride (II) (10 mmol),halogenated aralkylketone (12 mmol), potassium iodide (1 mmol) andanhydrous K₂CO₃ (35 mmol) in DMF (50 ml) was stirred at 25° C.-50° C.for 8-12 hour, filtrated, and then evaporated to dryness, 50 ml of waterwas added to the residue, and extracted with EtOAc (100 ml×30). Thecombined organic layer was washed with saline, dried (mgSO₄). Filteredand evaporated, the residue was dissolved by 30 ml of ethanol and thenadjusted to pH=2 with HCl/C₂H₅OH (5N); the resulting precipitate wasrecrystallized from ethanol or CH₃OH to obtain the title compound (III)(60-85%).

General Preparation 3: N¹-aralky-N⁴-arylalkanol piperazinedihydrochloride (IV)

A mixture of N¹-aralkyl-N⁴-arylformoxylalkyl piperazine dihydrochloride(III) (3.5 mmol) and KHCO₃ (8.75 mmol) in methanol (60 ml) was addedKBH₄ (14 mmol), and stirred at room temperature for 2 h, and thenrefluxed for 3-5 hours. Adjusted to a PH of 8 by 1 N aqueous NaOH andthen filtered. The filtrate was extracted with EtOAC (40 ml×30), washedwith saline, evaporated to dryness, which was dissolved in 20 ml ofethanol, and adjusted to PH=2 with HCl/C₂H₅OH (5N), the resultingprecipitate was recrystallized from ethanol to obtain the title compound(60-80%).

Example 1

IV-1 N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol) piperazine dihydrochloride

A mixture of N-benzylpiperazine dihydrochloride (7 mmol) and2-bromo-1-phenylpropan-1-one (8.4 mmol) was treated according to thegeneral preparation 2 to obtain N¹-benzyl-N⁴-(1-benzoylethyl) piperazinedihydrochloride (2.6 g, 5 mmol), which was reduced according to thegeneral preparation 3 to obtain 1.28 g of the title compound, yield 67%,mp 244-246° C.).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.68, H 7.49, N 7.18);theoretical value (% C 62.66, H 7.36, N 7.31).

IR (KCl): ν 3240, 2980, 1450, 1030

¹HNMR (DMSO-d₆): δ 0.99 (m, 3H, NCHCH₂), 3.44-3.92 (m, 9H, N—CH,piperazine-H), 4.40 (s, 2H, PhCH₂), 5.52 (br, 1H, PhCHOH), 7.24-7.67 (m,10H, ArH).

MS: m/z 311, 221, 204

Example 2

IV-2 N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3-ol) piperazinedihydrochloride

First of all, a mixture of 4-chlorobenzylchlorine and piperazine wastreated according to the general preparation 1 to obtainN-(4-chlorobenzyl) piperazine dihydrochloride, yield 65%, mp 278-280° C.Then, a mixture of the above product (5 g, 20 mmol), KHCO₃ (70 mmol) and2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of ethanol wasrefluxed for 8 hours, and then treated according to the generalpreparation 2 to obtain 6.1 g of N¹-(4-chlorobenzyl)-N⁴-(1-benzoylethyl)piperazine dihydrochloride, yield 59.51%, mp 260-262° C. Finally, amixture of above compound (1.5 g, 3.45 mmol) and KBH₄ (0.74 g, 14 mmol)was treated according to the general preparation 3 to obtain the titlecompound, yield 65%, mp. 240° C.).

Elementary analysis: C₂₀H₂₅ClN₂O.2HCl.2H₂O. Found: (% C 54.74, H 6.71, N6.34); theoretical value (% C 55.12, H 6.71, N 6.43).

MS: m/z 344 (M)⁺

Example 3

IV-3 N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol) piperazinedihydrochloride

The N¹-(1-phenylethyl)-N⁴-(1-benzoylethyl) piperazine (1.42 g, 3.5 mmol)could be preparated according to the general preparation 2, and thenreduced according to the general preparation 3 to obtain 0.86 g of thetitle compound, yield 62%, mp. 232-233° C.).

Elementary analysis: C₂₁H₂₈N₂O.2HCl. Found: (% C 63.39, H 7.65, N 7.00);theoretical value (% C 63.47, H 7.61, N 7.05).

IR (KCl)° C. ν 3260, 2960, 1480, 1020

¹HNMR (DMSO-d₆): δ 0.97 (d, J=6.6, 3H, NCHCH₃), 1.72 (d, J=7.2, 3H,PhCHCH₃), 3.46-4.00 (m, 9H, N—CHCH₃, piperazine-H), 4.63 (br, 1H,PhCHN), 5.50 (br, 1H, PhCHOH), 7.23-7.67 (m, 10H, ArH).

MS: m/z 325 (M+H)⁺ 221, 185

Example 4

IV-4 N¹-benzyl-N⁴-[2-(4-chlorophenyl)ethyl-2-ol] piperazinedihydrochloride

The N¹-benzyl-N⁴-(4-chlorobenzoylmethyl) piperazine dihydrochloride (1.2g, 3 mmol) could be preparated according to the general preparation 2,and then reduced according to the general preparation 3 to obtain 0.91 gof the title compound, yield 75%, mp. 240-242° C.).

Elementary analysis: C₁₉H₂₃ClN₂O.2HCl. Found: (% C 56.39, H 6.35, N7.00); theoretical value (% C 56.52, H 6.24, N 6.94).

MS: m/z 331 (M⁺)

Example 5

IV-5 N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol) piperazinetrihydrochloride

A mixture of 3-chloromethylpyridine and piperazine hexahydrate wastreated according to the general preparation 1 to obtainN-(3-pyridylmethyl) piperazine trihydrochloride (62%). A mixture of theabove product (3 mmol) and 2-chloro-1-phenylethanol (3.2 mmol) wastreated according to the general preparation 2 to obtain theN¹-(3-pyridylmethyl)-N⁴-phenacyl piperazine trihydrochloride (0.85 g, 2mmol), which was reduced according to the general preparation 3 toobtain 0.61 g of the title compound, yield 72%, mp. 180-182° C.).

Elementary analysis: C₁₈H₂₃N₃O.3HCl.H₂O. Found: (% C 51.05, H 6.45, N9.95); theoretical value (% C 50.92, H 6.65, N 9.89).

MS: m/z 297 (M⁺)

Example 6

IV-6 N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

A mixture of 4-fluorobenzylchlorine and piperazine was treated accordingto the general preparation 1 to obtain N-(4-fluorobenzyl) piperazinedihydrochloride (67%), mp, 282-284° C. TheN¹-(4-fluorobenzyl)-N⁴-phenacyl piperazine dihydrochloride could bepreparated according to the general preparation 2, which was reducedwith KHCO₃ (0.65 g, 6.5 mmol) and KBH₄ (0.59 g, 10.4 mmol) in methanol(40 ml) according to the general preparation 3 to obtain 0.72 g of thetitle compound as white solid.

Elementary analysis: C₁₉H₂₃FN₂O.2HCl. Found: (% C 58.81, H 6.35, N7.28); theoretical value (% C 58.92, H 6.51, N 7.23).

MS: m/z 314 (M⁺)

Example 7

IV-7 N¹-benzyl-N⁴-[2-(4-nitrophenyl)ethyl-2-ol] piperazinedihydrochloride

The N¹-benzyl-N⁴-(4-nitrophenacyl) piperazine dihydrochloride (0.84 g, 2mmol) could be preparated according to the general preparation 2, andthen reduced according to the general preparation 3 to obtain 0.60 g ofthe title compound, yield 70%, mp. 238-241° C.).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl.½H₂O. Found: (% C 54.05, H 6.25, N9.85); theoretical value (% C 53.91, H 6.19, N 9.93).

MS: m/z 314 (M⁺)

Example 8

IV-8 N¹-benzyl-N⁴-[(1,2-diphenyl)ethyl-2-ol] piperazine dihydrochloride

The N¹-benzyl-N⁴-(1-phenylbenzoylmethyl) piperazine dihydrochloride (2g, 4.5 mmol) could be preparated according to the general preparation 2.A mixture of the above compound, KHCO₃ (10 mmol) and KBH₄ (10.4 mmol) inmethanol (40 ml) was treated according to the general preparation 3 toobtain 1.2 g of the title compound as white solid, mp. 256-258° C.

Elementary analysis: C₂₅H₂₈N₂O.2HCl.H₂O. Found: (% C 65.04, H 6.80, N5.67); theoretical value (% C 64.79, H 6.96, N 6.05).

MS: m/z 372 (M⁺)

Example 9

IV-9 N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl)ethyl-2-ol] piperazinedihydrochloride

A mixture of 4-nitrobenzylchlorine and piperazine was treated accordingto the general preparation 1 to obtain N-(4-nitrobenzyl) piperazinedihydrochloride, yield 64%, mp 242-244° C. TheN¹-(4-nitrobenzyl)-N⁴-[(4-acetamido) phenacyl] piperazinedihydrochloride (0.75 g, 1.5 mmol) could be preparated according to thegeneral preparation 2, and then reduced according to the generalpreparation 3 to obtain 0.61 g of the title compound, yield 80%, mp150-151° C.).

Elementary analysis: C₂₁H₂₆N₄O₄.2HCl.2H₂O. Found: (% C 49.55, H 6.25, N11.15); theoretical value (% C 49.71, H 6.36, N 11.04).

MS: m/z 372 (M⁺)

Example 10

IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl)ethyl-2-ol] piperazinedihydrochloride

The N¹-benzyl-N⁴-[(4-acetamido) phenacyl] piperazine dihydrochloridecould be synthesized according to the general preparation 2, and thenreduced according to the general preparation 3 to obtain the titlecompound, yield 75%, mp 144-146° C.

Elementary analysis: C₂₁H₂₇N₃O₂.2HCl.2H₂O. Found: (% C 54.35, H 7.20, N9.15); theoretical value (% C 54.54, H 7.19, N 9.08).

MS: m/z 353 (M⁺)

Example 11

IV-11 N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2-ol] piperazinedihydrochloride

The N¹-(4-fluorobenzyl)-N⁴-(4-chlorophenacyl) piperazine dihydrochloride(0.87 g, 2 mmol) could be preparated according to the generalpreparation 2, and then reduced according to the general preparation 3to obtain 0.65 g of the title compound, yield 76%, mp 236-238° C.).

Elementary analysis: C₁₉H₂₂ClFN₂O.2HCl.½H₂O. Found: (% C 53.05; H5.75,N6.65); theoretical value (% C 52.98, H 5.85, N 6.50).

MS: m/z 348 (M⁺)

Example 12

IV-12 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

The N¹-[1-(4-nitrophenyl)ethyl]-N⁴-phenacyl piperazine dihydrochloridewas preparated according to the general preparation 2, and then reducedaccording to the general preparation 3 to obtain the the title compound,yield 76%, mp 220-222° C.

Elementary analysis: C₂₀H₂₅N₃O₃.2HCl.H₂O. Found: (% C 53.95, H 6.45, N9.35); theoretical value (% C 53.81, H 6.55, N 9.41).

MS: m/z 355 (M⁺)

Example 13

IV-13 N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

The N¹-(3-methoxybenzyl)-N⁴-phenacyl piperazine (0.36 g, 1.1 mmol) couldbe preparated according to the general preparation 2. A mixture of abovecompound, KHCO₃ (0.28 g, 2.8 mmol) and KBH₄ (0.24 g, 4.4 mmol) inmethanol (20 ml) was treated according to the general preparation 3 toobtain 0.24 g of the title compound as white solid.

Elementary analysis: C₂₀H₂₆N₂O₂Cl.2HCl. Found: (% C 60.31, H 6.93, N7.14); theoretical value (% C 60.15, H 7.07, N 7.02).

MS: m/z 326 (M⁺)

Example 14

IV-14 N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol)piperazinedihydro-chloride

The N¹-(2-nitro-5-methoxybenzyl)-N⁴-phenacyl piperazine dihydrochloridecould be preparated according to the general preparation 2, and thenreduced according to the general preparation 3 to obtain the titlecompound, yield 72%.

Elementary analysis: C₂₀H₂₅N₃O₄.2HCl. Found: (% C 53.98, H 6.25, N9.35); theoretical value (% C 54.06, H 6.12, N 9.46).

MS: m/z 371 (M⁺)

Example 15

IV-15 N¹-[1-(4-nitrophenyl)ethyl]-N⁴-[2-(4-methylphenyl)ethyl-2-ol]piperazine dihydrochloride

A mixture of N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(4-methylphenacyl)piperazine dihydrochloride (2 g, 4.54 mmol), KHCO₃ (1 g, 9.99 mmol) andKBH₄ (0.98 g, 18.17 mmol) in methanol (60 ml) was treated according tothe general preparation 3 to obtain 1.54 g of the title compound aswhite solid.

Elementary analysis: C₂₁H₂₇N₃O₃.2HCl. Found: (% C 57.31, H 6.63, N9.54); theoretical value (% C 57.01, H 6.61, N 9.50).

MS: m/z 369 (M⁺)

Example 16

IV-16 N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl-2-ol]piperazine dihydrochloride

A mixture of N-benzylpiperazine dihydrochloride (2 g, 9.4 mmol),2-bromo-1-(5-chloro-6-methoxynaphthalen-1-yl) ethanone (3.54 g, 11.3mmol) and K₂CO₃ (4.55 g, 33 mmol) in acetone (120 ml) was treatedaccording to the general preparation 2 to obtainN¹-benzyl-N⁴-(5-chloro-6-methoxy-2-naphthoylmethyl) piperazinedihydro-chloride (2.85 g). The above product (2.6 g, 30 mmol) wasreduced with NaBH₄ (2.22 g, 60 mmol) in methanol (150 ml) according tothe general preparation 3 to obtain 10.2 g of the title compound aswhite solid.

Elementary analysis: C₂₄H₂₇ClN₂O₂.2HCl. Found: (% C 59.61, H 6.03, N5.61); theoretical value (% C 59.65, H 6.05, N 5.80).

MS: m/z 410 (M⁺)

Example 17

IV-17N¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

A mixture of N-(3-chlorophenyl) piperazine dihydrochloride (1.35 g, 5mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.96g, 6 mmol) and K₂CO₃ (2.42 g, 17.5 mmol) in DMF (40 ml) was treatedaccording to the general preparation 2 to obtain 1.65 g ofN¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride, yield 64%. The above product was reducedwith NaBH₄ in methanol (50 ml) according to the general preparation 3 toobtain the title compound as white solid, yield 78%.

Elementary analysis: C₂₄H₂₆Cl₂N₂O₂.2HCl. Found: (% C 55.31, H 5.52, N5.53); theoretical value (% C 55.61, H 5.45, N 5.41).

MS: m/z 445 (M⁺)

Example 18

IV-18N¹-(2-phenylethyl-2-ol)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

The N¹-phenacyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazinedi-hydrochloride could be preparated according to the generalpreparation 2, and then reduced according to the general preparation 3to obtain the title compound, yield 70%.

Elementary analysis: C₂₆H₃₁Cl N₂O₃.2HCl. Found: (% C 59.31, H 6.09, N5.41); theoretical value (% C 59.15, H 6.30, N 5.31).

MS: m/z 455 (M⁺), 129, 111

Example 19

IV-19N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

This compound has the formula as defined in claim 1, wherein R₁ is H, R₂is CH₃; X is CHOH; Ar₁ is phenyl, Ar₂ is 5-chloro-6-methoxy-2-naphthyl;n=m=1.

A mixture of N-benzyl piperazine dihydrochloride (1.5 g, 7.05 mmol),2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-one (2.8 g, 8.5mmol) and triethyl-amine (2.38 g, 23.5 mmol) in benzene (150 ml) wastreated according to the general preparation 2 to obtain 2.14 g ofN¹-benzyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazinedihydrochloride, yield 60%, mp 252-253° C.).

To a mixture of the above product (1 g, 2 mmol) and KHCO₃ (0.5 g, 5mmol) in methanol (50 ml) was added KBH₄ (0.44 g, 8 mmol), stirred atroom temperature for 2 h, and then refluxed for 3 h, adjusted to pH=2with 1 N aqueous NaOH and then filtered. The filtrate was extracted withEtOAC (40 ml×3), washed with saline, evaporated to dryness, which wasdissolved in 20 ml of ethanol, and adjusted to pH=2 with HCl/C₂H₅OH. Theresulting precipitate was recrystallized with ethanol (95%) to obtainthe title compound, yield 75%. Content (HPLC): 99.80%.

Elementary analysis: C₂₅H₂₉ClN₂O₃.2HCl. Found: (% C 58.41, H 6.12, N5.51); theoretical value (% C 58.43, H 6.08, N 5.45).

¹HNMR (DMSO-d₆): δ 0.97 (d, 3H, NCHCH₃), 2.81-2.93 (m, 9H, N—CHCH₃,piperazine-H), 4.02 (s, 3H, OCH₃), 5.32 (br, 1H, PhCHOH), 7.34-8.14 (m,10H, ArH).

MS: m/z 425 (M+H)⁺, 407

Example 20

IV-20N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

The N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride (0.24 g, 0.5 mmol) could be preparatedaccording to the general preparation 2, and then reduced with NaBH₄ (0.2g, 5 mmol) in methanol (30 ml) according to the general preparation 3 toobtain 0.14 g of the title compound as white solid.

Elementary analysis: C₂₅H₂₈Cl N₃O₄.2HCl. Found: (% C 55.25, H 5.59, N7.51); theoretical value (% C 55.31, H 5.57, N 7.74).

MS: m/z 470 (M⁺)

Example 21

IV-21N¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine trihydrochloride

A mixture ofN¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine trihydrochloride (0.08 g, 1.83 mmol) and NaBH₄ (0.1 g) inmethanol (20 ml) was treated according to the general preparation 3 toobtain 0.05 g of the title compound as white solid.

Elementary analysis: C₂₅H₃₂Cl N₃O₂.3HCl. Found: (% C 54.31, H 6.53, N7.54); theoretical value (% C 54.56, H 6.23, N 7.64).

MS: m/z 441 (M⁺)

Example 22

IV-22N¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

A mixture ofN¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride (0.8 g, 1.4 mmol) and NaBH₄ (0.155 g, 4.1mmol) in methanol (20 ml) was treated according to the generalpreparation 3 to obtain 0.19 g of the title compound as white solid, mp:226-228° C.

Elementary analysis: C₂₈H₃₅Cl N₂O₅.2HCl. Found: (% C 57.31, H 6.63, N4.54); theoretical value (% C 57.20, H 6.34, N 4.77).

MS: m/z 541 (M⁺)

Example 23

IV-23 N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

A mixture of 4-methoxybenzylchlorine and piperazine was treatedaccording to the general preparation 1 to obtain N-(4-methoxybenzyl)piperazine dihydrochloride, yield 75%, mp. 250-252° C. TheN¹-(4-methoxybenzyl)-N⁴-phenacyl piperazine dihydrochloride (0.5 g, 1.23mmol) could be preparated according to the general preparation 2, andthen reduced according to the general preparation 3 to obtain 0.38 g ofthe title compound, yield 77.55%, mp 244-246° C.).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C 59.84, H 7.04, N6.83); theoretical value (% C 60.15, H 7.07, N 7.02).

IR (KCl): ν 3340, 2980, 1620, 1040

MS: m/z 327 (M+H)⁺, 208, 185

Example 24

IV-24 N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2-ol) piperazinedihydrochloride

A solution of S-(+)-mandelic acid (10 mmol) in acetylchloride (30 mmol),was stirred at 25° C. for 12 hours, and then evaporated to dryness. Theresidue was dissolved in DMF (20 ml) and then addedN-ethyl-N-isopropylpropan-2-amine (11 mmol) and C₂H₅O₂CC (CN)═NOC[N(CH₃)₂]═N(CH₃)₂BF₄ (11 mmol) at 0° C. under N₂, stirred at the sametemperature for 1 hour. After the addition ofN-(4-methoxybenzyl)piperazine (10 mmol), the reaction mixture wasstirred at 25° C. for 24 hours. and then evaporated to dryness, whichwas diluted in water (20 ml) and chloroform (50 ml). The organic phasewas washed with water, NaHCO₃, 5% citric acid and saline (10 ml), dried(mgSO₄), filtered and then evaporated to obtainN¹-(4-methoxybenzyl)-N⁴-(1-oxo-S-2-phenylethyl-2-ol) piperazine as oil,directly used in the next step.

A mixture of above compound (50 mmol) and LiAlH₄ (125 mmol) in THF (150ml) was refluxed for 2 hours, added Na₂SO₄ (6 g), and then stirred for 1hour. After filtration, the filtrate was adjusted to pH=2 withHCl/C₂H₅OH, the resulting precipitate was recrystallized with ethanol toobtain the title compound, yield 75%, mp 223-224° C. [α]_(D) ²⁰+12.9 (c1, H₂O).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C 60.23, H 7.11, N6.61); theoretical value (% C 60.15, H 7.07, N 7.02).

¹HNMR (DMSO-d₆): 3.57 (m, 10H, NCH₂, piperazine-H), 3.77 (s, 3H, OCH₃),4.34 (s, 2H, PHCH₂), 5.14 (m, 1H, PhCHOH), 6.99-7.59 (m, 9H, ArH).

MS: m/z 327 (M+H)⁺, 207

Example 25

IV-25 N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2-ol) piperazinedihydrochloride

Using R-(−)-mandelic acid and N-(4-methoxybenzyl) piperazine in thesimilar procedure of example 24 to obtain the title compound, mp238-239° C., [α]_(D) ²⁰−13.1 (c 1, H₂O).

Elementary analysis: C₂₀H₂₆N₂O₂.2HCl. Found: (% C 60.34, H 7.17, N6.58); theoretical value (% C 60.15, H 7.07, N 7.02).

¹HNMR (DMSO-d₆): δ 3.52 (m, 10H, NCH₂, piperazine-H), 3.77 (s, 3H,OCH₃), 4.33 (s, 2H, PHCH₂), 5.14 (t, 1H, PhCHOH), 6.99-7.59 (m, 9H,ArH).

MS: m/z 327 (M+H)⁺, 207, 185

Example 26

IV-26 N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

The N¹-(4-nitrobenzyl)-N⁴-phenacyl piperazine dihydrochloride (0.5 g,1.21 mmol) could be preparated according to the general preparation 2,and then reduced according to the general preparation 3 to obtain 0.3 gof the title compound, mp 242-243° C.).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl.½H₂O. Found: (% C 53.84, H 6.04, N10.03); theoretical value (% C 53.90, H 6.19, N 9.93).

MS: m/z 342 (M+H)⁺

Example 27

IV-27 N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol) piperazinedihydrochloride

Using S-(+)-mandelic acid (22 mmol) and N-benzylpiperazine (20 mmol) asstarting materials to prepareN¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine dihydrochloride in thesimilar procedure of example 24.

A mixture of the above product (1.8 g, 4.88 mmol) and 10% Pd—C (0.2 g)in HAc (40 ml) was passed hydrogen at 70% for 3 hours, and filtered thenevaporated to dryness. The residue was dissolved in ethanol (20 ml),adjusted solution to pH=2 with HCl/C₂H₅OH, recrystallized with ethanol(95%) to obtain 1.14 g of N-(2S-phenylethyl-2-ol) piperazinedihydrochloride, yield 85%.

A mixture of N-(S-2-phenylethyl-2-ol) piperazine dihydrochloride (4.1mmol) and 4-nitrobenzylchlorine (0.77 g, 4.49 mmol) was treatedaccording to the general preparation 2 to obtain the title compound,yield 47%, mp. 214-216° C. [α]_(D) ²⁰+14.0 (c 1, H₂O).

Elementary analysis: C₁₉H₂₃N₃O₃.2HCl 1H₂O. Found: (% C 53.02, H 5.93, N7.69); theoretical value (% C 52.78, H 6.29, N 7.72).

¹HNMR (DMSO-d₆): δ3.52-3.80 (br, 10H, NCH₂, piperazine-H), 4.49 (s, 2H,PHCH₂), 5.14 (m, 1H, PhCHOH), 7.28-8.32 (m, 9H, ArH).

MS: m/z 342 (M+H)⁺, 185

Example 28

IV-28 N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol) piperazinedihydrochloride

Using R-(−)-mandelic acid and N-benzyl piperazine as starting materialsto prepare N-(R-2-phenylethyl-2-ol) piperazine dihydrochloride in thesimilar procedure of example 27. A mixture of the above compound and4-nitrobenzylchlorine was treated according to the general preparation 2to obtain the title compound, yield 48%, mp 239-241° C. [α]_(D) ²⁰ −7.1(c 1, H₂O).

Elementary analysis: C₁₉H₂₃N₂O₃.2HCl. Found: (% C 54.66, H 6.06, N10.09); theoretical value (% C 55.08, H 6.08, N 10.14).

¹HNMR (DMSO-d₆): δ 3.52 (br, 10H, NCH₂, piperazine-H), 4.48 (s, 2H,PHCH₂), 5.14 (t, 1H, PhCHOH), 7.28-8.31 (m, 9H, ArH).

MS: m/z 342 (M+H)⁺, 207, 185

Example 29

IV-29 N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

Using N¹-(1-phenylethyl)-N⁴-phenacyl piperazine (IIV-37) (1.5 g, 3.9mmol) as a starting material, and then reduced according to the generalpreparation 3 to obtain 1 g of the title compound, mp 254-255° C.).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.43, H 7.38, N 7.18);theoretical value (% C 62.66, H 7.36, N 7.31).

MS: m/z 310 (M⁺)

Example 30

IV-30 N¹-(R-1-phenethyl)-N⁴-(R-2-phenylethyl-2-ol) piperazinedihydrochloride (1) N-(R-1-phenethyl) piperazine dihydrochloride

A mixture of chloroacetic acid (94.5 g) and 32.2 ml ofR-1-phenylethylamine in 125 ml of 8N NaOH was reacted at 70□ for 10hours, and added a solution of BaCl₂ (65 g) in 200 ml of water dropwise,and then refluxed for 1 hour. After filtration, the solid was put into400 ml of water and then added 100 ml of 5N H₂SO₄, refluxed for 1 hour,filtered and washed with water, the filtrate was evaporated in vacuo togive N,N-di(hydroxyformyl)-(R)-1-phenylethylamine.

A mixture of the above product and 80 ml of formamide in 80 ml of Xylenewas refluxed for 8 hours, and then extracted with EtOAC (100 ml×2). Thecombined organic layer was washed with water, concentrated in vacuo toobtain (R)-4-(1-phenylethyl) piperazine-2,6-dione as colorless crystals.Yield 72% (two steps).

A mixture of (R)-4-(1-phenylethyl)piperazine-2,6-dione (10.9 g, 50 mmol)and LiAlH₄ (4.75 g, 125 mmol) in 150 ml of THF was refluxed for 2 hours,and then added Na₂SO₄ (6 g), stirred for 1 hour, filtered and washedwith EtOAC, the filtrate was adjusted to pH=2 with HCl/C₂H₅OH. Theresulting precipitate was recrystallized from ethanol to giveN-(R-1-phenylethyl) piperazine dihydrochloride, yield 85%. [α]²⁰_(D)+22.40° (c=1, MeOH). MS: m/z 190 (M⁺).

(2) Using the above product (10 mmol) and R-(−)-mandelic acid (12 mmol)in the similar procedure of example 24 to obtain the title compound, mp247-248° C., [α]_(D) ²⁰−18.58 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.95, H 7.50, N 7.23);theoretical value (% C 62.66, H 7.36, N 7.31).

IR (KBr): 3260, 2970, 1460, 760, 710 cm⁻¹.

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.39-3.70 (m, 10H, NCH₂,piperazine-H), 4.55-4.61 (m, 1H, NCH), 5.13-5.16 (m, 1H, PhCHOH),7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 31

IV-31 N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2-ol) piperazinedihydrochloride

Using N-(R-1-phenethyl) piperazine (10 mmol) and S-(+)-mandelic acid (12mmol) in the similar procedure of example 24 to obtain the titlecompound, mp 242-244° C., [α]_(D) ²⁰+48.72 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.75, H 7.60, N 7.43);theoretical value (% C 62.66, H 7.36, N 7.31).

IR (KBr): 3260, 2980, 1440, 760, 710 cm⁻¹

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.40-3.73 (m, 10H, NCH₂,piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH),7.38-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 32

IV-32 N¹-(S-1-phenethyl)-N⁴-(S-2-phenylethyl-2-ol) piperazinedihydrochloride

Using (S)-phenylethyla mine as a starting material to prepareN¹-(S-1-phenethyl) piperazine dihydrochloride in the similar procedureof example 30, [α]_(D) ²⁰−22.50° (c=1, MeOH). The above product (10mmol) was reacted with S-(+)-mandelic acid (12 mmol) in the similarprocedure of example 24 to obtain the title compound, mp 247-248□,[α]_(D) ²⁰ +18.21 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.38, H 7.41, N 7.24);theoretical value (% C 62.66, H 7.36, N 7.31).

IR (KBr): 3260, 2985, 1450, 760, 710 cm⁻¹.

¹HNMR (DMSO-d₆): δ 1.76-1.78 (d, 3H, CH₃), 3.38-3.69 (m, 10H, NCH₂,piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH),7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 33

IV-33 N¹-(S-1-phenethyl)-N⁴-(R-2-phenylethyl-2-ol) piperazinedihydrochloride

Using R-(−)-mandelic acid (12 mmol) and N-(S-1-phenethyl) piperazine (10mmol) in the similar procedure of example 24 to obtain the titlecompound, mp 230-232° C., [α]_(D) ²⁰−48.42 (c 1, CH₃OH).

Elementary analysis: C₂₀H₂₆N₂O.2HCl. Found: (% C 62.50, H 7.49, N 7.44);theoretical value (% C 62.66, H 7.36, N 7.31).

IR (KBr): 3260, 2985, 1450, 760, 710 cm⁻¹.

¹HNMR (D₂O): δ 1.76-1.78 (d, 3H, CH₃), 3.40-3.73 (m, 10H, NCH₂,piperazine-H), 4.56-4.61 (m, 1H, NCH), 5.12-5.15 (m, 1H, PhCHOH),7.37-8.53 (m, 10H, ArH)

MS: m/z 311 (M+H)⁺, 207, 191, 103

Example 34

IV-34N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

A mixture ofN¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride (2.55 g, 5 mmol) and NaBH₄ (1.9 g, 51 mmol)in methanol (20 ml) was treated according to the general preparation 3to obtain 1.2 g of the title compound as white solid.

Elementary analysis: C₂₆H₃₁ClN₂O₅.2HCl. Experimental: (% C 61.21, H6.63, N 5.54); theoretical value (% C 61.00, H 6.50, N 5.47).

MS: m/z 439 (M+H)⁺

Example 35

IV-35N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine dihydrochloride

The title compound was prepared by usingN¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride (2.55 g, 5 mmol) in the similar procedure ofexample 34.

Example 36

Tablet: The compound in this invitation 10 mg Sucrose 150 mg Corn starch38 mg Calcium stearate 2 mg

Preparation: A mixture of the active constituent, sucrose and cornstarch in water was well stirred, and then dried and sifted, which wasmixed with Calcium stearate evenly, and tableted. Each tablet is 200 mgcontaining 10 mg of the active compound.

Example 37

Injection: The compound in this invitation 20 mg Physiological saline 80mg

Preparation: The active constituent was dissolved in physiologicalsaline, and then mixed evenly and filtered. The obtained clear solutionwas filled separately into ampoules under the aseptic condition, and thecomposition of each ampoule is weight of 10 mg, which containing 2 mg ofthe active compound.

Example 38

Antidepressant Effect of the Compounds

1. Inhibitory effects of compounds on uptaking serotonin (5-HT) andnoradrenaline (NA) by brain synaptosomes:

The trial of uptaking the mono-amines neurotransmitter by synaptosomesis now one of the common method to study the central nervouspharmacology. This method is not only used to study the action mechanismof the medicament, but also to look for new antidepressant drugs whichact on this tache. This method is used in the present invention, andselected Fluoxetine which is an inhibitor of 5-HT uptake and Desipramine which is an inhibitor of NA uptake as control drugs to study theeffects of invented compounds for inhibiting uptake of 5-HT and NA bybrain synaptosomes. The method is recounted as follows:

(1). Preparation of synaptosomes. According to the described method byliteratures (a. Biochem Pharmacol 1973, 22: 311-322, b. Methods inNeurochemistry, Vol. 2, New York: Marcel Dakker, Inc, 1972, 1-52), ratswere decapitated, the brains rapidly excised, and frontal cortexdissected out on ice-cold saline (4° C.). The 3 g tissue was homogenizedin 30 ml of ice-cold 0.32M sucrose and then centrifuged (1500 g) for 10min (4° C.). The pellet was discarded and the supernatant centrifuged(20000 g) for 30 min (4° C.). After refined, the pellet was resuspendedin buffer and immediately used. Protein content was deter mined with kitof total protein.

(2). Uptake of 5-HT. According to the described method by literatures(Br J Pharmacol, 1997, 122: 302-306; b. 1992, 105: 147-151), in thetubes, 1.0 ml artificial cerebral fluid, 20 μl suspension ofsynaptosomes and 10 μl solution of compound were added. After mixing,the tubes were incubated 5 min in 37° C. Uptake was started by additionof 10 μl [³H]-5-HT or [³H]-NA (300 nM), after another mixing, the tubeswere incubated again 5 min in 37° C. The reaction was stopped by coolingthe tubes in ice, the samples were then filtered through glass fibrefilters and washed twice with artificial cerebral fluid. After drying in60-70° C., the filter membranes were put into scintillation tubes.Filter-bound radioactivity was counted by scintillation spectrometry.The difference in [³H]-5-HT or [³H]-NA at 37° C. and 0° C. was taken asa measure of active uptake.

(3). Results: Under the same concentration (0.1 mmol/L for Fluoxetineand compounds), inhibited ratios of uptake 5-HT by Fluoxetine, and ofuptake NA by Desipra mine count 100%, the results were setting out inTable 3.

TABLE 3 Inhibitive Effects of Compounds on Brain Synaptosome Uptake of5-HT and NA Inhibited ratio of Inhibited ratio Compounds uptake for5-HT(%) of uptake for NA(%) IV-2 82 62 IV-4 85 51 IV-6 79 107 IV-8 <10104 IV-11 81 101 IV-17 99 30 IV-18 127 23 IV-19 114 140 IV-20 110 108IV-22 116 77 IV-26 63 80 IV-34 108 10 IV-35 107 58 Fluoxetine 100Desipra mine 100

Using the tail suspension test of “behavioural despair” and the mouseforced swimming test, and choosing Desipra mine as control medicament,to study the primary antidepressant effect of IV-19 that has the stronginhibited effect for both uptake of 5-HT and NA. The results are asfollows:

(1). In the tail suspension test, IV-19 can diminish obviously theimmobile times of mouse due to despair. The effect induced by 50 mg/kgIV-19 (20.2±16.05 sec) is the same as 10 mg/kg Desipra mine (27.5±21.93sec), but a significant difference occurs when comparing with control(89.7±38.27).

(2). In the mouse forced swimming test, IV-19 also can diminishobviously the immobile times of mouse in water due to despair. As theresults of tail suspension test, the effect induced by 50 mg/kg IV-19(46.3±30.2 sec) is the same as 10 mg/kg Desipra mine (46±27.36 sec), buta significant difference occurs when comparing with control(93.4±27.36).

3. Acute toxicity:

LD₅₀ of VI-19 (p.o. in mice) is about 1 g/kg calculated with Bliss.

4. Bacterial reverse-mutation assay (Ames TS) of IV-19

Bacillus: S. Typhimurium TA₉₇, TA₉₈, TA₁₀₀ and TA₁₀₂

Results: The assay includes two parts of without S₉ and with S₉, in thesystem without S₉ TA₉₈ 5000 μg/utensil, and with S₉ TA₉₇ 5000 μg/utensilhave the inhibitory effect for the growth of bacterial. The other doseshaven't inhibitory effect for all bacteria, the growth of bacteria iswell. All tested doses didn't induce the evident increase of revertants,Ames TS of V-19 is negative.

1. A compound of formula I:

wherein Ar₁ and Ar₂ independently represent:

R₁, R₂ and R₃ each represents hydrogen, a C₁-C₃ alkyl group, a C₅ or C₆cycloalkyl group, a phenyl, substituted phenyl, methoxy, ethoxy, amino,substituted amino, halogen, carboxylic acid, carboxylic ester, nitryl oracetonitrile group; Y represents C, N, or O; Z represents a five orsix-member carbocyclic ring, or a five or six-member heterocyclic ringwhere at least one carbon is replaced by S, N or O; n represents 1, 2 or3; m represents 1, 2 or 3; in the form of a free base or a salt thereof.2. A compound according to claim 1, wherein the salt is selected fromthe group consisting of hydrochloride, hydrobromide, sulfate,trifluoroacetate and methanesulfonate.
 3. A compound according to claim2, wherein the salt is hydrochloride or hydrobromide.
 4. A compoundaccording to claim 2, wherein the salt comprises about 0.5-3 moleculesof hydrate water.
 5. A compound according to claim 1, wherein R₁, R₂ andR₃ represents independently of each other hydrogen, a C₁-C₃ alkyl,methoxy, ethoxy, amino, substituted amino, halogen, or nitryl group. 6.A compound according to claim 1, in the form of a racemic mixture.
 7. Acompound according to claim 1, in the form of a pure enantiomer, or amixture of enantiomers in a non-racemic ratio.
 8. The compound of claim1, selected from the group consisting of: IV-1N¹-benzyl-N⁴-(phenylpropane-2-yl-3-ol)piperazine, IV-2N¹-(4-chlorobenzyl)-N⁴-(phenylpropane-2-yl-3 -ol)piperazine, IV-3N¹-(1-phenylethyl)-N⁴-(phenylpropane-2-yl-3 -ol)piperazine, IV-4N¹-benzyl-N⁴-[2-(4-chlorophenyl)ethyl-2-ol]piperazine, IV-5N¹-(3-pyridylmethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-6N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-7N¹-benzyl-N⁴-[2-(4-nitrophenyl)ethyl-2-ol]piperazine, IV-8N¹-benzyl-N⁴-[(1,2-diphenyl)ethyl-2-ol]piperazine, IV-9N¹-(4-nitrobenzyl)-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine,IV-10 N¹-benzyl-N⁴-[2-(4-acetamidophenyl)ethyl-2- ol]piperazine, IV-11N¹-(4-fluorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2- ol]piperazine, IV-12N¹-[1-(4-nitrophenyl)ethyl]-N⁴-(2-phenylethyl-2- ol)piperazine, IV-13N¹-(3-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-14N¹-(2-nitro-5-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-15N¹-[1-(4-nitrophenyl)ethyl]-N⁴-[2-(4-methylphenyl)ethyl-2-ol]piperazine, IV-16N¹-benzyl-N⁴-[2-(5-chloro-6-methoxy-2-naphthyl)ethyl- 2-ol]piperazine,IV-17 N¹-(3-chlorophenyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-18N¹-(2-phenylethyl-2-ol)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-19N¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-20N¹-(4-nitrobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-21N¹-(4-aminobenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-22N¹-(3,4,5-trimethoxybenzyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-23N¹-(4-methoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-24N¹-(4-methoxybenzyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-25N¹-(4-methoxybenzyl)-N⁴-(R-2-phenylethyl-2- ol)piperazine, IV-26N¹-(4-nitrobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-27N¹-(4-nitrobenzyl)-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-28N¹-(4-nitrobenzyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-29N¹-(1-phenylethyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-30N¹-(R-1-phenylethyl)-N⁴-(R-2-phenylethyl-2- ol)piperazine, IV-31N¹-(R-1-phenylethyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-32N¹-(S-1-phenylethyl)-N⁴-(S-2-phenylethyl-2- ol)piperazine, IV-33N¹-(S-1-phenylethyl)-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-34N¹-(S-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-35N¹-(R-1-phenylethyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine, IV-36N¹-benzyl-N⁴-(2-phenylethyl-2-ol)piperazine, IV-37N¹-(4-chlorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-38N¹-(4-chlorobenzyl)-N⁴-[2-(4-chlorophenyl)ethyl-2- ol]piperazine, IV-39N¹-benzyl-N⁴-[2-(4-methoxyphenyl)ethyl-2- ol]piperazine, IV-40N¹,N⁴-di(2-phenylethyl-2-ol)-piperazine, IV-41N¹-(4-aminobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-42N¹-benzyl-N⁴-[(2-naphthyl)ethyl-2-ol]piperazine, IV-43N¹-benzyl-N⁴-[(3-phenyl)propyl-3-ol]piperazine, IV-44N¹-(2,4-dimethoxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-45N¹-benzyl-N⁴-(S-2-phenylethyl-2-ol)piperazine, IV-46N¹-benzyl-N⁴-(R-2-phenylethyl-2-ol)piperazine, IV-47N¹-(1-phenylpropyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-48N¹-(4-fluorobenzyl)-N⁴-(2-phenylethyl-2-ol)piperazine, IV-49N¹-(3,4-methylenedioxybenzyl)-N⁴-(2-phenylethyl-2- ol)piperazine, IV-50N¹-(1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, IV-51N¹-(S-1-phenylethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine, andIV-52 N¹-(R-1-phenethyl)-N⁴-[2-(4-methylphenyl)ethyl-2- ol]piperazine.


9. The compound according to claim 7, which isN¹-benzyl-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol]piperazine.10. A pharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable excipient.
 11. A method for treatingdepression, the method comprising administering to a patient in needthereof an effective amount of the pharmaceutical composition accordingto claim 10.